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Background: Altered gut metabolites, especially short-chain fatty acids (SCFAs), in feces and plasma are observed in patients with Parkinson's disease (PD). Objective: We aimed to investigate the colonic expression of two SCFA receptors, free fatty acid receptor (FFAR)2 and FFAR3, and gut barrier integrity in patients with PD and correlations with clinical severity. Methods: In this retrospective study, colonic biopsy specimens were collected from 37 PD patients and 34 unaffected controls. Of this cohort, 31 participants (14 PD, 17 controls) underwent a series of colon biopsies. Colonic expression of FFAR2, FFAR3, and the tight junction marker ZO-1 were assayed by immunofluorescence staining. The You Only Look Once (version 8, YOLOv8) algorithm was used for automated detection and segmentation of immunostaining signal. PD motor function was assessed with the Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (UPDRS), and constipation was assessed using Rome-IV criteria. Results: Compared with controls, PD patients had significantly lower colonic expression of ZO-1 (p < 0.01) and FFAR2 (p = 0.01). On serial biopsy, colonic expression of FFAR2 and FFAR3 was reduced in the pre-motor stage before PD diagnosis (both p < 0.01). MDS-UPDRS motor scores did not correlate with colonic marker levels. Constipation severity negatively correlated with colonic ZO-1 levels (r = -0.49, p = 0.02). Conclusions: Colonic expression of ZO-1 and FFAR2 is lower in PD patients compared with unaffected controls, and FFAR2 and FFAR3 levels decline in the pre-motor stage of PD. Our findings implicate a leaky gut phenomenon in PD and reinforce that gut metabolites may contribute to the process of PD. [ABSTRACT FROM AUTHOR]

Bronchial asthma is a chronic respiratory disease characterized by reversible airflow limitation, including airway hyperresponsiveness, airway inflammation and airway remodeling. The clinical manifestations are recurrent tachypnea, wheezing, dyspnea, cough and other manifestations, which seriously affect the life of patients. The incidence of asthma increases the social and economic burden. Many researchers have reported the role of free fatty acid receptors (FFARs) in diseases such as bronchial asthma, colitis, arthritis and other diseases. Free fatty acids are ligands of FFARs. GPR40, GPR41, GPR43, GPR120 and GPR84 have been identified as FFARs. There are many studies on fatty acids and asthma. However, whether this represents the role of FFARs needs further study. FFARs can affect the occurrence and progression of asthma through β-arrestins, RhoA/ROCK1, PLC/IP3, MAPK, AMPK and other pathways. This article reviews the research progress on the role of FFARs in bronchial asthma, with the aim of providing a reference for their use as new targets for the treatment of bronchial asthma. [ABSTRACT FROM AUTHOR]

FFA4 has gained interest in recent years since its deorphanization in 2005 and the characterization of the Free Fatty Acids receptors family for their therapeutic potential in metabolic disorders. The expression of FFA4 (also known as GPR120) in numerous organs throughout the human body makes this receptor a highly potent target, particularly in fat sensing and diet preference. This offers an attractive approach to tackle obesity and related metabolic diseases. Recent cryo‐EM structures of the receptor have provided valuable information for a potential active state although the previous studies of FFA4 presented diverging information. We performed molecular docking and molecular dynamics simulations of four agonist ligands, TUG‐891, Linoleic acid, α‐Linolenic acid, and Oleic acid, based on a homology model. Our simulations, which accumulated a total of 2 μs of simulation, highlighted two binding hotspots at Arg992.64 and Lys293 (ECL3). The results indicate that the residues are located in separate areas of the binding pocket and interact with various types of ligands, implying different potential active states of FFA4 and a highly adaptable binding intra‐receptor pocket. This article proposes additional structural characteristics and mechanisms for agonist binding that complement the experimental structures. [ABSTRACT FROM AUTHOR]

Bronchial asthma is a chronic respiratory disease characterized by reversible airflow limitation, including airway hyperresponsiveness, airway inflammation and airway remodeling. The clinical manifestations are recurrent tachypnea, wheezing, dyspnea, cough and other manifestations, which seriously affect the life of patients. The incidence of asthma increases the social and economic burden. Many researchers have reported the role of free fatty acid receptors (FFARs) in diseases such as bronchial asthma, colitis, arthritis and other diseases. Free fatty acids are ligands of FFARs. GPR40, GPR41, GPR43, GPR120 and GPR84 have been identified as FFARs. There are many studies on fatty acids and asthma. However, whether this represents the role of FFARs needs further study. FFARs can affect the occurrence and progression of asthma through β-arrestins, RhoA/ROCK1, PLC/IP3, MAPK, AMPK and other pathways. This article reviews the research progress on the role of FFARs in bronchial asthma, with the aim of providing a reference for their use as new targets for the treatment of bronchial asthma.

AbstractThis study aimed to investigate the impact of Free-fatty acid receptor-4 (FFAR4) rs61866610 polymorphism on colorectal cancer (CRC) risk. Herein, ninety-two histopathologically confirmed CRC patients and 95 healthy individuals were evaluated for FFAR4 polymorphism by RFLP-PCR. Gender, age, body mass index (BMI), underlying disease, and smoking status were recorded for all subjects. Clinical and histopathologic findings including tumor grade and TNM stage were also prepared in the patient group. Except for type 2 diabetes which was more prevalent in the control group, there were no differences between the two groups regarding underlying diseases (p > 0.05). The frequency of genotypes was as follows: in the CRC group 75% wild type, 23.9% heterozygous, and 1.1% homozygous mutant. In the control group 85.3% wild type, 12.6% heterozygous, and 2.1% homozygous mutant. Mutant allele carriers were more frequent in CRC subjects (25%) than in the normal group (14.7%) but it did not reach a significant level. The frequency of mutant genotypes in colon cancer and rectal cancer was 27.5% and 8.3% respectively (p = 0.282). The mutant genotypes were found more in patients with high-grade tumors (p = 0.154). Subjects with stage III/IV had a higher frequency of mutant genotypes than low-stage cases (p = 0.011). No association was found regarding rs61866610 and obesity or type 2 diabetes (p > 0.05). In conclusion, FFAR4 (rs61866610) has no significant association with the risk of CRC, but the higher frequency of mutant genotypes in subjects with advanced cancer stages (III/IV) suggests further studies to determine the role of FFAR4 in colorectal tumorigenesis. [ABSTRACT FROM AUTHOR]

Abstract G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1β and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1β. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions.

G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1β and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1β. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions. Highlights: GPR120 is enriched in murine and human microglia. Central GPR120 agonism decreases microglia activation and anxiety- and sickness-like behaviors in response to LPS. GPR120 agonism attenuates nucleus accumbens microglia reactivity and behavioral responses to central cytokine administration. [ABSTRACT FROM AUTHOR]

Eicosapentaenoic acid and docosahexaenoic acid are n-3 fatty acids that are highly available in sea-fishes. Many studies have revealed that n-3 fatty acids play antidiabetic activity. In this study antidiabetic activity of the three sea fishes oils, 'volavetki' (Panna microdon, Bleeker 1849), 'ruli' (Coilia dussumieri, Valenciennes 1848), and 'tapra' (Opisthopterus tardoore, Cuvier 1829), as well as three fresh-water fishes oils, 'bata' (Labeo bata, Hamilton 1822), 'folui' (Opisthopterus tardoore, Cuvier 1829), and 'mourala' (Amblypharyngodon mola, Hamilton 1822) evaluated high lipid diet (HLD) and STZ-induced type 2 diabetes mellitus (T2DM) rats. The GC-MS analysis revealed high n-3 fatty acid content in volavetki oil. Supplementation of sea-fish oils and antidiabetic effect was monitored by fasting plasma blood glucose and HbA1c. Also, insulin, c-peptide, glucagon-like peptide-1, dipeptidyl peptidase-4, free fatty acid receptor 1, glucokinase, glucose-6 phosphatase, superoxide dismutase, glutathione peroxidase, catalase, malondialdehyde, plasma total cholesterol, low density lipoprotein, triglycerides, high density lipoprotein, c-reactive protein, total protein, alkaline phosphatase, and histopathology of pancreatic tissues were evaluated. Out of six fish oils, oral supplementation with volavetki oil resulted in significant reduction of plasma blood glucose, HbA1c of T2DM rat. All other parameters in T2DM rats were returned to near normally by treatment of volavetki oil. These findings strongly indicate that volavetki oil possess antidiabetic activity. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases.

The tumor microenvironment (TME) comprises cancer and non-cancerous stromal cells, including fibroblasts. Free fatty acids (FFAs) regulate various biological responses by binding to G protein-coupled FFA receptors (FFARs). In this study, we examined the impact of FFAR1 and FFAR4 on the cell migration of pancreatic cancer PANC-1 cells co-cultured with 3T3 fibroblast cells under hypoxic conditions. PANC-1 cells cultured at 1 % O 2 exhibited elevated FFAR1 expression and decreased FFAR4 expression compared to those at 21 % O 2. Cell migration of PANC-1 cells was reduced under 1 % O 2 conditions. FFAR1 knockdown enhanced PANC-1 cell migration, whereas FFAR4 knockdown inhibited it. Co-culture of PANC-1 cells with 3T3 cells at 1 % O 2 significantly increased FFAR4 expression, while FFAR1 expression remained unchanged. To evaluate the effects of FFAR1 and FFAR4 on PANC-1 cell migration in co-culture with 3T3 cells, we conducted a wound healing assay using the Culture-Insert 2 Well. PANC-1 and 3T3 cells were individually seeded into the two wells and incubated at both 21 % and 1 % O 2 for 13 h. The cell migration of PANC-1 cells co-cultured with 3T3 cells at 1 % O 2 was notably higher compared to 21 % O 2. TUG-770 reduced and TUG-891 enhanced the cell migration of PANC-1 cells co-cultured with 3T3 cells under both 21 % and 1 % O 2 conditions. These findings suggest that FFAR1 and FFAR4 play important roles in regulating the cell migration of PANC-1 cells co-cultured with 3T3 cells under hypoxic conditions. • Cell migration of PANC-1 cells was reduced by culturing at 1 % O 2 , compared with 21 % O 2. • FFAR1 inhibits and FFAR4 stimulates the cell migration of PANC-1 cells. • FFAR4 expression was higher in PANC-1 cells at 1 % O 2 than in PANC-1 cells cultured at 21 % O 2. • Cell migration of PANC-1 cells co-cultured with 3T3 fibroblast cells at 1 % O 2 was elevated. • FFARs regulate the cell migration of PANC-1 cells co-cultured with 3T3 cells under hypoxic conditions. [ABSTRACT FROM AUTHOR]

Transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1, respectively) channels contribute to inflammatory and neuropathic pain, indicating that their pharmacological inhibition could be a novel strategy for treating painful diseases. However, the mechanisms of TRPA1/V1 channel modulation have been mostly characterized to be upregulation and sensitization via variety of exogenous stimuli, endogenous inflammatory mediators, and metabolites of oxidative stress. Here we used calcium imaging of dorsal root ganglion neurons to identify an inhibitor signaling pathway for TRPA1 and TRPV1 regulated by resolvins (RvD1 and RvE1), which are endogenous anti‐inflammatory lipid mediators. TRPA1 and TRPV1 channel activations were evoked by the TRPA1 agonist allyl isothiocyanate and the TRPV1 agonist capsaicin. Our results show that RvD1‐induced selective inhibition of TRPA1 activity was mediated by free fatty acid receptor 4 (FFAR4)‐protein kinase C (PKC) signaling. Experiments assessing RvE1‐induced TRPV1 inhibition showed that RvE1 actions required both FFAR1 and FFAR4. Combined stimulation of FFAR1/FFAR4 or FFAR1/PKC mimicked TRPV1 inhibition by RvE1, and these effects were blocked by a protein kinase D (PKD) inhibitor, implying that PKD is an effector of the FFAR/PKC signaling axis in RvE1‐induced TRPV1 inhibition. Despite selective inhibition of TRPV1 in the nanomolar range of RvE1, higher concentrations of RvE1 also inhibited TRPA1, possibly through PKC. Collectively, our findings reveal FFAR1 and FFAR4 as key signaling pathways mediating the selective targeting of resolvins to regulate TRPA1 and TRPV1, elucidating endogenous analgesic mechanisms that could be exploited as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Gut microbiota plays an important role in metabolic homeostasis. Previous studies demonstrated that ginsenoside Rb1 might improve obesity-induced metabolic disorders through regulating glucose and lipid metabolism in the liver and adipose tissues. Due to low bioavailability and enrichment in the intestinal tract of Rb1, we hypothesized that modulation of the gut microbiota might account for its pharmacological effects as well. Here, we show that oral administration of Rb1 significantly decreased serum LDL-c, TG, insulin, and insulin resistance index (HOMA-IR) in mice with a high-fat diet (HFD). Dynamic profiling of the gut microbiota showed that this metabolic improvement was accompanied by restoring of relative abundance of some key bacterial genera. In addition, the free fatty acids profiles in feces were significantly different between the HFD-fed mice with or without Rb1. The content of eight long-chain fatty acids (LCFAs) was significantly increased in mice with Rb1, which was positively correlated with the increase of Akkermansia and Parasuttereller , and negatively correlated with the decrease of Oscillibacter and Intestinimonas. Among these eight increased LCFAs, eicosapentaenoic acid (EPA), octadecenoic acids, and myristic acid were positively correlated with metabolic improvement. Furthermore, the colonic expression of the free fatty acid receptors 4 (Ffar4) gene was significantly upregulated after Rb1 treatment, in response to a notable increase of LCFA in feces. These findings suggested that Rb1 likely modulated the gut microbiota and intestinal free fatty acids profiles, which should be beneficial for the improvement of metabolic disorders in HFD-fed mice. This study provides a novel mechanism of Rb1 for the treatment of metabolic disorders induced by obesity, which may provide a therapeutic avenue for the development of new nutraceutical-based remedies for treating metabolic diseases, such as hyperlipidemia, insulin resistance, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Gut microbiota plays an important role in metabolic homeostasis. Previous studies demonstrated that ginsenoside Rb1 might improve obesity-induced metabolic disorders through regulating glucose and lipid metabolism in the liver and adipose tissues. Due to low bioavailability and enrichment in the intestinal tract of Rb1, we hypothesized that modulation of the gut microbiota might account for its pharmacological effects as well. Here, we show that oral administration of Rb1 significantly decreased serum LDL-c, TG, insulin, and insulin resistance index (HOMA-IR) in mice with a high-fat diet (HFD). Dynamic profiling of the gut microbiota showed that this metabolic improvement was accompanied by restoring of relative abundance of some key bacterial genera. In addition, the free fatty acids profiles in feces were significantly different between the HFD-fed mice with or without Rb1. The content of eight long-chain fatty acids (LCFAs) was significantly increased in mice with Rb1, which was positively correlated with the increase of Akkermansia and Parasuttereller, and negatively correlated with the decrease of Oscillibacter and Intestinimonas. Among these eight increased LCFAs, eicosapentaenoic acid (EPA), octadecenoic acids, and myristic acid were positively correlated with metabolic improvement. Furthermore, the colonic expression of the free fatty acid receptors 4 (Ffar4) gene was significantly upregulated after Rb1 treatment, in response to a notable increase of LCFA in feces. These findings suggested that Rb1 likely modulated the gut microbiota and intestinal free fatty acids profiles, which should be beneficial for the improvement of metabolic disorders in HFD-fed mice. This study provides a novel mechanism of Rb1 for the treatment of metabolic disorders induced by obesity, which may provide a therapeutic avenue for the development of new nutraceutical-based remedies for treating metabolic diseases, such as hyperlipidemia, insulin resistance, and type 2 diabetes.

In health, commensal bacteria from oral biofilms stimulate polymorphonuclear neutrophil (PMN) recruitment in gingival sulci and the oral cavity. Oral PMN (oPMN) is short-lived cells with low prosurvival gene expression. In periodontitis, oPMN accumulates in higher numbers, has extended lifespan, and sustains nonresolving inflammation. We hypothesize that short- and long-chain free fatty acids (SCFAs and LCFAs) and lipid mediator resolvin E1 (RvE1) modulate host ability to control biofilms and resolve inflammation. Our objective was to measure oPMN surface expression of receptors FFAR2 (binds bacteria-derived SCFA), FFAR4 (binds LCFA, EPA, and DHA), and ERV1 (binds RvE1) in health and to assess sex differences. We included 20 periodontally healthy individuals aged 20–80 years (10 males, 10 females), who were asked to (1) answer a targeted health nutritional questionnaire and (2) provide an oral saline rinse. oPMN isolated by sequential filtration was labeled with fluorophore-conjugated antibodies against CD11b, CD14, CD16, CD66b, ERV1, FFAR2, and FFAR4 and analyzed by flow cytometry. Statistical analyses were the following: two-way ANOVA, Tukey's test, and Pearson's correlation. Oral rinses contained 80% oPMN of which 60% were ERV1+ and FFAR2+, and 10% FFAR4+, with no sex differences. Females had more oPMN ERV1 compared to males. Both sexes had higher ERV1 compared to FFAR2 and FFAR4. CD66b+CD16high oPMN expressed less ERV1 and FFAR2 compared to CD66b+CD16low. There were positive correlations between oPMN ERV1 and FFAR2 expression and between ERV1+ and FFAR2+ oPMN and fish intake. These findings will help to better understand how oral host and microbiome interactions maintain periodontal health.

Free fatty acid receptors (FFARs) are a class of G protein-coupled receptors (GPCRs) that have wide-ranging effects on human physiology. The four well-characterized FFARs are FFAR1/GPR40, FFAR2/GPR43, FFAR3/GPR41, and FFAR4/GPR120. Short-chain (

Free fatty acid receptors (FFARs) are a class of G protein-coupled receptors (GPCRs) that have wide-ranging effects on human physiology. The four well-characterized FFARs are FFAR1/GPR40, FFAR2/GPR43, FFAR3/GPR41, and FFAR4/GPR120. Short-chain (<6 carbon) fatty acids target FFAR2/GPR43 and FFAR3/GPR41. Medium- and long-chain fatty acids (6–12 and 13–21 carbon, respectively) target both FFAR1/GPR40 and FFAR4/GPR120. Signaling through FFARs has been implicated in non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), intestinal failure-associated liver disease (IFALD), and a variety of other liver disorders. FFARs are now regarded as targets for therapeutic intervention for liver disease, diabetes, obesity, hyperlipidemia, and metabolic syndrome. In this review, we provide an in-depth, focused summary of the role FFARs play in liver health and disease. [ABSTRACT FROM AUTHOR]

Cholecystokinin (CCK) is secreted from enteroendocrine I cells in response to fat, carbohydrate, and protein ingestion. Gene expression of nutrient-sensing molecules in I cells remains unclear, primarily due to the difficulty in distinguishing I cells from intestinal epithelial cells in vivo. In this study, we generated CCK reporter male mice in which t he red fluorescence protein tdTomato (Tomato) is produced by activation of the native murine Cck promoter. Fluorescence microscopy revealed the presence of Tomato-positive cells in upper small intestine (SI), lower SI, and colon. Flow cytometer analysis revealed that Tomato-positive cells among epithelial cells of upper SI, lower SI, and colon occurred at the rate of 0.95, 0.54, and 0.06%, respectively. In upper SI and lower SI, expression levels of Cck mRNA were higher in Tomato-positive cells than those in Tomato -negative cells. The fatty acid receptors Gpr120, Gpr40, and Gpr43 and the oleoylethanolamide receptor Gpr119 were highly expressed in Tomato-positive cells isolated from SI, but were not found in Tomato-positive cells from colon. The glucose and fructose transporters Sglt1, Glut2, and Glut5 were expressed in both Tomato-positive cells and -negative cells, but these expression levels tended to be decreased in Tomato-positive cells from upper SI to colon. The peptide transporter Pept1 and receptor Gpr93 were expressed in both Tomato-positive cells and -negative cells, whereas Casr was expressed only in Tomatopositive cells isolated from SI. Thus, this transgenic mouse reveals that I cell number and gene expression in I cells vary according to region in the gast rointestinal tract. [ABSTRACT FROM AUTHOR]

Long-chain fatty acids activate the free fatty acid receptor 1 (FFA1) and FFA4. In the gastrointestinal system, FFA1 and FFA4 have been found in the pancreas and intestine. Fatty food and decreased lower esophageal sphincter (LES) motility are associated with gastroesophageal reflux disease. The effect of long-chain fatty acids on the esophageal motility is unknown. The purpose of this study is to investigate the effects of long-chain fatty acids on the porcine LES motility ex vivo using isometric transducers. In endothelin 1-precontracted porcine LES strips, the FFA1 selective agonists, fasiglifam, TUG424, and GW9508, caused marked relaxations in a concentration-dependent manner. The relative efficacies to elicit relaxation were GW9508 > TUG424 > fasiglifam in both clasp and sling strips. In contrast, the FFA4 specific agonists, TUG891 and GSK137647, produced mild relaxations. In addition, the endogenous FFA1 agonist DHA caused a mild relaxation whereas GW1100, an FFA1 antagonist, inhibited GW9508 induced relaxation of the porcine LES clasp and sling muscle. Both real-time PCR and immunohistochemistry revealed that FFA1 and FFA4 were expressed in the porcine LES. Real-time PCR analysis showed that the FFA4 expression was much lower than FFA1. Taken together, long-chain fatty acid receptor agonists elicit relaxation of the porcine LES. FFA1 might influence LES motility.

Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids’ synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

Obesity is a major risk factor for the development of asthma, and worsens the key features of asthma including airway hyperresponsiveness, inflammation, and airway remodeling. Although pro- and anti-inflammatory adipocytokines may contribute to the pathogenesis of asthma in obesity, the mechanistic basis for the relationship between asthma and obesity remains unclear. In obese individuals, the increased amount of adipose tissue results in the release of more long-chain free fatty acids as compared to lean individuals, causing an elevation in plasma long-chain free fatty acid concentrations. Recent findings suggest that the free fatty acid receptor 1 (FFAR1), which is a sensor of medium- and long-chain free fatty acids, is expressed on airway smooth muscle and plays a pivotal role in airway contraction and airway smooth muscle cell proliferation. In contrast, FFAR4, which is a sensor for long-chain n -3 polyunsaturated fatty acids and also expressed on airway smooth muscle, does not contribute to airway contraction and airway smooth muscle cell proliferation. Functional roles for short-chain fatty acid receptors FFAR2 and FFAR3 in the pathogenesis of asthma is still under debate. Taken together, adipose-derived long-chain free fatty acids may contribute to the pathogenesis of asthma in obesity through FFAR1. [ABSTRACT FROM AUTHOR]

Long-chain fatty acids activate the free fatty acid receptor 1 (FFA1) and FFA4. In the gastrointestinal system, FFA1 and FFA4 have been found in the pancreas and intestine. Fatty food and decreased lower esophageal sphincter (LES) motility are associated with gastroesophageal reflux disease. The effect of long-chain fatty acids on the esophageal motility is unknown. The purpose of this study is to investigate the effects of long-chain fatty acids on the porcine LES motility ex vivo using isometric transducers. In endothelin 1-precontracted porcine LES strips, the FFA1 selective agonists, fasiglifam, TUG424, and GW9508, caused marked relaxations in a concentration-dependent manner. The relative efficacies to elicit relaxation were GW9508 > TUG424 > fasiglifam in both clasp and sling strips. In contrast, the FFA4 specific agonists, TUG891 and GSK137647, produced mild relaxations. In addition, the endogenous FFA1 agonist DHA caused a mild relaxation whereas GW1100, an FFA1 antagonist, inhibited GW9508 induced relaxation of the porcine LES clasp and sling muscle. Both real-time PCR and immunohistochemistry revealed that FFA1 and FFA4 were expressed in the porcine LES. Real-time PCR analysis showed that the FFA4 expression was much lower than FFA1. Taken together, long-chain fatty acid receptor agonists elicit relaxation of the porcine LES. FFA1 might influence LES motility. [ABSTRACT FROM AUTHOR]

Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids' synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes. [ABSTRACT FROM AUTHOR]

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancing of glucose‐stimulated insulin secretion. The FFA1 agonist GW9508 has great potential for the treatment of type 2 diabetes mellitus, but it has been suffering from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β‐oxidation. To identify orally available analog without influence on the unique pharmacological mechanism of GW9508, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α‐position of phenylpropionic acid affording compound 4 (HWL‐066). As expected, HWL‐066 revealed a lower clearance (CL = 0.23 L−1 hr−1 kg−1), higher maximum concentration (Cmax = 5907.47 μg/L), and longer half‐life (T1/2 = 3.50 hr), resulting in a 2.8‐fold higher exposure than GW9508. Moreover, the glucose‐lowering effect of HWL‐066 was far better than that of GW9508 and comparable with TAK‐875. Different from glibenclamide, no side‐effect of hypoglycemia was observed in mice after oral administrating HWL‐066 (80 mg/kg). [ABSTRACT FROM AUTHOR]

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda’s compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18 , which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration ( C max  = 7584.27 μg/L), and longer half-life ( T 1/2  = 4.16 h), resulting in a >23-fold exposure than compound 1 . In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

Fatty acid metabolism contributes to energy supply and plays an important role in regulating immunity. Free fatty acids (FFAs) bind to free fatty acid receptors (FFARs) on the cell surface and mediate effects through the intra-cellular FFAR signaling pathways. FFAR4, also known as G-protein coupled receptor 120 (GPR120), has been identified as the primary receptor of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). FFAR4 is a promising target for treating metabolic and inflammatory disorders due to its immune regulatory functions and the discovery of highly selective and efficient agonists. This review summarizes the reported immune regulatory functions of ω-3 PUFAs and FFAR4 in immune cells and immune-related diseases. We also speculate possible involvements of ω-3 PUFAs and FFAR4 in other types of inflammatory disorders. [ABSTRACT FROM AUTHOR]

GPR84 is a G protein-coupled receptor for mediumchain fatty acids. Capric acid and 3,3'-diindolylmethane are specific agonists for GPR84. We built a homology model of a GPR84-capric acid complex to investigate the ligand-binding mode using the crystal structure of human active-state β2-adrenergic receptor. We performed site-directed mutagenesis to subject ligandbinding sites to our model using GPR84-Gia fusion proteins and a [35S]GTPγS-binding assay. We compared the activity of the wild type and mutated forms of GPR84 by [35S]GTPcS binding to capric acid and diindolylmethane. The mutations L100D 'Ballesteros-Weinstein numbering: 3.32), F101Y (3.33) and N104Q (3.36) in the transmembrane helix III and N357D (7.39) in the transmembrane helix VII resulted in reduced capric acid activity but maintained the diindolylmethane responses. Y186F (5.46) and Y186H (5.46) mutations had no characteristic effect on capric acid but with diindolylmethane they significantly affected the G protein activation efficiency. The L100D (3.32) mutant responded to decylamine, a fatty amine, instead of a natural agonist, the fatty acid capric acid, suggesting that we have identified a mutated G protein-coupled receptor-artificial ligand pairing. Our molecular model provides an explanation for these results and interactions between GPR84 and capric acid. Further, from the results of a double stimulation assay, we concluded that diindolylmethane was a positive allosteric modulator for GPR84. [ABSTRACT FROM AUTHOR]

Free fatty acids (FFAs) are energy-generating nutrients that act as signaling molecules in various cellular processes. Several orphan G protein-coupled receptors (GPCRs) that act as FFA receptors (FFARs) have been identified and play important physiological roles in various diseases. FFA ligands are obtained from food sources and metabolites produced during digestion and lipase degradation of triglyceride stores. FFARs can be grouped according to ligand profiles, depending on the length of carbon chains of the FFAs. Medium- and long-chain FFAs activate FFA1/GPR40 and FFA4/GPR120. Short-chain FFAs activate FFA2/GPR43 and FFA3/GPR41. However, only medium-chain FFAs, and not long-chain FFAs, activate GPR84 receptor. A number of pharmacological and physiological studies have shown that these receptors are expressed in various tissues and are primarily involved in energy metabolism. Because an impairment of these processes is a part of the pathology of obesity and type 2 diabetes, FFARs are considered as key therapeutic targets. Here, we reviewed recently published studies on the physiological functions of these receptors, primarily focusing on energy homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: The free fatty acid receptor FFA1, FFA2, and FFA3 and hydroxy-carboxylic acid receptor (HCA2) are G protein–coupled receptors, acting as energy and metabolic sensors. Herein, we characterized the tissue-specific mRNA abundance of genes encoding for these receptors at different stages of lactation. In addition, potential effects of supplementation with or without conjugated linoleic acids (CLA) were tested. Tissues from pluriparous cows (subcutaneous adipose tissue [SAT] and liver) and from primiparous cows (3 SAT locations, 3 visceral adipose tissues, liver, mammary gland, and skeletal muscle) were used from 2 separate trials. In primiparous cows, the mRNA abundance of all receptors (FFA3 was not detectable by the applied protocol in muscle and udder) was lowest in muscle (P < 0.05). With the exception of FFA1, gene expression of the investigated receptors was higher in adipose tissue than in the non-adipose tissue. Expression of FFA1 in liver (P < 0.03), FFAR2 in SAT (P < 0.01), and HCA2 in SAT (P < 0.01) from pluriparous cows changed during the observation period (days 21 to 252 relative to parturition). The correlation between mRNA abundance of HCA2 and peroxisome proliferator–activated receptor gamma (PPARG) and likewise PPARG2 (P < 0.01) in SAT indicates a link between HCA2 and PPARG. Differences in receptor mRNA abundance between the CLA-fed and the control animals were scarce and limited to HCA2 and FFA1 in 1 and 2 time points, respectively (less hepatic HCA2 mRNA in CLA-fed pluriparous cows and greater FFA1 mRNA abundance in 2 visceral adipose tissue depots in CLA-treated primiparous cows). In view of the metabolic changes occurring during the different phases of lactation, in particular, the altered concentrations of non-esterified fatty acids and β-hydroxybutyrate acting as receptor ligands, the longitudinal tissue-specific characterization provided herein allows for a first insight into the regulation of these receptors at the gene expression level. [Copyright &y& Elsevier]